Progression-free Survival Research Articles

Optimizing Treatment Strategies for Egfr-Mutated Non-Small-Cell Lung Cancer Treated with Osimertinib: Real-World Outcomes and Insights

Background: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), demonstrated superior efficacy over first-generation TKIs in the FLAURA trial, resulting in its approval as first-line therapy for metastatic non-small-cell lung cancer (NSCLC). However, the real-world application of these trial results requires an evaluation of sequential therapeutic strategies. Methods: This retrospective, non-interventional study utilized data from the Epidemiological Strategy and Medical Economics (ESME) platform, which includes information on patients treated for lung cancer since 2015. Out of 39,974 patients in the database, 624 patients with EGFR-mutant advanced NSCLC treated with osimertinib as first-line (L1, n = 198) or second-line (L2, n = 426) treatment after first- or second-generation TKIs (n = 1262) were identified. Patient demographics, disease characteristics, treatment strategies, and disease progression were examined. Survival analyses were performed using Kaplan–Meier estimates and Cox proportional-hazards models. Results: In the study population (n = 624), 73.4% were female, with a median age of 70 years (range 28–93). Brain metastases at the start of osimertinib treatment were observed in 282 patients. ECOG PS-2 was reported in 29.4% of patients. The T790M mutation in exon 20 was identified in 257/426 patients (60.3%) receiving osimertinib in L2. Median progression-free survival (PFS) was 12.4 months (95% CI [10.7–14.7]) for L1 and 7.4 months (95% CI [6.2–8.7]) for L2. Median overall survival (OS) from advanced diagnosis was 28.5 months (95% CI [26.3–38.7]) for osimertinib L1 and 29.9 months (95% CI [28.6–31.8]) for osimertinib L2 (HR = 0.93; 95% CI [0.75–1.16]; p = 0.50). For L1, median OS was 27.1 months (95% CI [22.0–30.2]) for patients with cerebral metastases and 38.7 months (95% CI [26.3–52.8]) for those without (HR = 0.73; 95% CI [0.48–1.11]; p = 0.15). Discussion: Patients in the real-world ESME database exhibited a poorer prognosis compared to those in the FLAURA trial. The presence of cerebral metastases at diagnosis worsens the prognosis.

Circulating DNA in Rectal Cancer to Unravel the Prognostic Potential for Radiation Oncologist: A Meta-analysis.

Liquid biopsy, with its noninvasive nature and ability to detect tumor-specific genetic alterations, emerges as an ideal biomarker for monitoring recurrences for locally advanced rectal cancer (LARC). Completed studies have small sample sizes and different experimental methods. To consolidate and assess the collective evidence regarding the prognostic role of circulating DNA (ctDNA) detection in LARC patients undergoing neoadjuvant chemoradiotherapy (nCRT). Computerized bibliographic searches of MEDLINE and CANCERLIT (2000 to 2023) were supplemented with hand searches of reference lists. Study selection: studies evaluating oncological outcomes of patients with LARC treated with a nCRT comparing patients with positive and negative liquid biopsy at baseline and after nCRT. Data extraction: data on population, intervention, and outcomes were extracted from each study, in accordance with the intention to treat method, by 2 independent observers, and combined using the DerSimonian method and Laird method. Nine studies follow inclusion criteria including 678 patients treated with nCRT. The pooled RD rate of ctDNA negative between measure at baseline and after nCRT is statistically significant 61% (95% CI: 53-70, P=0.0002). The hazard ratio (HR) of progression-free survival between ct-DNA negative and positive is significant 7.41 (95% CI: 4.87-11.289, P<0.00001). ctDNA can identify patients with different recurrence risks following nCRT and assess prognosis in patients with LARC. Further prospective study is necessary to determine the utility of ctDNA in personalised therapy for patients with LARC.

Differentiation fate of a stem-like CD4 T cell controls immunity to cancer.

The T cell response to cancer controls disease progression and response to immunotherapy1-3. Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here we identified a population of PD1+TCF1+ CD4 T cells with stem-like properties that are capable of self-renewal and differentiation into canonical CD4 effector cells. Primarily residing in tumour-draining lymph nodes (TDLNs), these tumour-specific CD4 T cells are restricted by T regulatory (Treg) cells to a stem-like fate that predominantly generated induced Treg (iTreg) cells, limiting effector CD8 T cell responses to the tumour. By contrast, upon Treg depletion, stem-like CD4 T cells differentiated into T helper 1 (TH1) cells, and via IFNγ production induced robust effector differentiation from TCF1+ CD8 T cells in TDLNs, a state we defined as 'active'. Notably, enforcing TBET expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of Treg cells, endogenous stem-like CD4 T cells actively generated TH1 cells, which were required to restore TDLN effector CD8 T cell differentiation, enhance tumour control and rescue response to immunotherapy. In agreement, TH1 differentiation in patients with kidney cancer predicted successful immunotherapy responses and improved progression-free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies.

In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data

BackgroundThere is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate.MethodsWe initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs).Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021.ResultsThe bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69–0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61–0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188).ConclusionsResearch on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs.

Safety and efficacy of DEB-TACE in combination with lenvatinib and camrelizumab for the treatment of unresectable hepatocellular carcinoma (uHCC): a two-centre retrospective study

ObjectivesThe purpose of this study was to compare the safety and efficacy of drug-eluting bead (DEB) transarterial chemoembolization combined with lenvatinib and camrelizumab (DEB-TACE-Len-C) and DEB-TACE-Len for the treatment of unresectable hepatocellular carcinoma (uHCC).MethodsThis retrospective study consecutively included uHCC patients who underwent DEB-TACE-Len-C or DEB-TACE-Len treatment at our hospital and Qujing Second People’s Hospital from April 2020 to April 2022. In total, 85 patients were enrolled. There were 42 patients in the DEB-TACE-Len-C group and 43 patients in the DEB-TACE-Len group. The disease control rate (DCR), objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared between the two groups, and the factors influencing OS and PFS were analysed.ResultsThe ORR, DCR, PFS and OS were significantly greater in the DEB-TACE-Len-C group than in the DEB-TACE-Len group (ORR: 76.2% vs. 46.5%, P = 0.005; DCR: 88.1% vs. 67.8%, P = 0.039; PFS: 10 months vs. 6 months, P &amp;lt;0.0001; OS: 24 months vs. 16 months, P = 0.0038). Multivariate Cox proportional hazard regression analysis revealed that portal tumour thrombus (PVTT) and therapeutic approach were independent factors affecting PFS and OS. There were no statistically significant differences in the incidence of AEs between the two groups (P &amp;gt; 0.05).ConclusionCompared with DEB-TACE-Len, DEB-TACE-Len-C is an effective treatment option that can improve the tumour therapeutic response and prolong the OS and PFS in uHCC patients.

Favorable Prognosis in Patients With Multiple Myeloma and Lenalidomide-Induced Skin Rash: A Multicenter Retrospective Study.

Although lenalidomide is an essential treatment for multiple myeloma (MM), skin rashes are a common adverse event. This retrospective study aimed to examine the association between skin rash development during lenalidomide treatment and the prognosis of relapsed/refractory MM. All patients who received lenalidomide at 10 hospitals between July 2009 and December 2015 were included in the study. The relationship of skin rash development with disease progression and survival was evaluated. Multivariate analysis was performed to identify factors affecting disease progression or survival, including skin rash. Of the 245 patients analyzed, 70 developed skin rashes. The median progression-free survival (PFS) of patients with skin rashes was 22.4 months, whereas the median PFS for patients who did not develop skin rashes was 10.5 months (p = 0.003). The median overall survival for patients with and without skin rash was 42.6 and 24.6 months, respectively (p = 0.013). Multivariate regression analysis showed that skin rash was an independent prognostic factor for PFS (p = 0.009). In this study, patients with skin rashes during lenalidomide treatment had significantly better PFS than those without such symptoms, indicating that lenalidomide-associated skin rashes may be a predictor of clinical outcomes in patients with MM.

Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy.

This study evaluated the prognostic value of basal and interim [68Ga]Ga-DOTA-TOC PET/CT in patients with locally advanced or metastatic neuroendocrine tumour (NET) who received peptide receptor radionuclide therapy (PRRT). Patients with NET who received PRRT with [177Lu]Lu-DOTA-TATE at our institution were retrospectively reviewed. Among them, patients who underwent both basal and interim (after two cycles of PRRT) [68Ga]Ga-DOTA-TOC PET/CT were included. Alongside clinicopathologic parameters, PET parameters of maximum standardised uptake value (SUVmax), tumour-to-liver ratio (TLR), whole tumour volume (WTV) and total receptor expression (TRE: WTV multiplied by mean standardised uptake value) were obtained from basal and interim [68Ga]Ga-DOTA-TOC PET/CT, and their proportional changes (∆) were assessed for associations with progression-free survival (PFS) using Kaplan-Meier analysis, log-rank tests, and a Cox proportional-hazards regression model. Twenty-four patients were finally included (10 men and 14 women, median age of 56.5 years, age range 32-74 years). Among them, 16 patients (66.7%) experienced disease progression. In univariate analysis, high ∆WTV (≥ -10%, hazard ratio [HR] = 3.053 [1.003-9.289], p = 0.049) and high ∆TRE (≥ -21%, HR = 3.567 [1.144-11.122], p = 0.028) were significantly associated with shorter PFS. In multivariate analyses adjusted for WHO grade, high ∆WTV (HR = 3.345 [1.055-10.601], p = 0.043) and high ∆TRE (HR = 3.894 [1.194-12.695], p = 0.024) were significant predictors of shorter PFS. The study demonstrates that basal and interim [68Ga]Ga-DOTA-TOC PET/CT scans, through proportional changes in WTV and TRE, effectively predict PFS in neuroendocrine tumour patients receiving PRRT. Question Peptide receptor radionuclide therapy is utilised for patients with somatostatin receptor-positive well-differentiated neuroendocrine tumours; however, prognostic predictors are not well established. Findings Progression-free survival was significantly associated with the proportional change in whole tumour volume and total receptor expression between basal and interim [68Ga]Ga-DOTA-TOC PET/CT. Clinical relevance Interim [68Ga]Ga-DOTA-TOC PET/CT can serve as a valuable imaging method to predict prognosis of peptide receptor radionuclide therapy.

Clinical impact of TP53 functional mutations in patients with metastatic colorectal cancer treated with bevacizumab and chemotherapy.

Clinical and experimental studies indicate that the tumor protein p53 (TP53) gene loss of function due to missense mutations (MMs) may confer sensitivity to anti-angiogenics. This effect seems to be linked to cross-talk mechanisms among TP53, vascular endothelial growth factor (VEGF), and VEGF receptors. We investigated whether specific TP53 MMs are associated with clinical outcomes of patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy plus Bevacizumab. The study focused on KRAS-mutated, liver-only mCRC cases as a homogeneous subgroup that may represent a relevant setting for exploring this association. MMs were identified on primary tumors. MMs were classified by mutant-specific residual transcriptional activity scores (TP53RTAS) as transcriptionally inactive (TP53inactive = TP53RTAS 0%) or active (TP53active = TP53RTAS ≥ 1%) and used for stratifying patients in progression-free survival (PFS), response rate, and overall survival (OS) analyses. The study population consisted of 62 patients. MMs were found in 39 cases (62%) with 16 having TP53inactive and 23 TP53active MMs. Patients with TP53inactive MMs showed better PFS in comparison with the remaining groups (wild-type and TP53active). This effect was retained in the multivariate model. A similar clinical impact was observed in the OS analysis. There was a significant difference in the overall response rate and rate of post-treatment resection of liver metastases between the TP53inactive and the wild-type or TP53active MMs cases. Specific TP53 MMs may identify sub-groups of patients who benefit from Bevacizumab-based systemic therapy and these findings could lead to novel tailored treatment strategies in this setting.

Association between Tumor Size at the Time of Disease Progression and Survival Outcomes.

This study evaluates the prognostic significance of tumor size at disease progression (PD) and depth of response (DOR) in cancer patients. We performed post hoc analysis using data from six prospective clinical trials conducted by the Korean Cancer Study Group. Patients with tumor size at PD was categorized into 'Mild PD' and 'Significant PD' based on the cutoff values of relative change from baseline using maximally selected rank statistics. The overall survival (OS) and progression-free survival (PFS) were compared between PD and DOR categories. Among the 194 evaluable patients, 130 experienced PD. A 35.48% decrease from baseline in tumor size at PD was chosen for the cutoff between mild and significant PD for OS (mild PD: tumor size from the baseline ≤ -35.48%; significant PD > -35.48%). The mild PD had superior OS compared to the significant PD (25.8 vs. 12.8 months; Hazard ratio [HR] 0.47, 95% CI 0.266-0.843, p=0.009). When using an exploratory cutoff based on whether the tumor size was below vs. exceeded from the baseline (mild PD: tumor size from the baseline ≤ 0%; significant PD > 0%), OS remained significantly longer in the mild PD (17.1 vs. 11.8 months; HR 0.60, 95% CI 0.392-0.932, p=0.021). The greatest DOR was associated with the longest OS and PFS (p<0.001 for both). Tumor size at PD and DOR were significant prognostic factors for progressive disease. Maintaining a sufficiently reduced tumor size even during PD was associated with better survival outcomes.

Prognostic Impact of Low Muscle Mass and Inflammatory Markers in Stage III Nonsmall Cell Lung Cancer Turkish Oncology Group and Turkish Society of Radiation Oncology Thoracic Cancer Study Group (08-005).

The aim of this retrospective multicenter study was to evaluate the prognostic significance of low muscle mass, and inflammatory markers in patients with stage III nonsmall cell lung cancer (NSCLC) who received definitive chemoradiotherapy (CRT). Furthermore, the study aimed to determine the threshold value of disease-specific low muscle mass. A total of 461 patients with stage III NSCLC were evaluated. Low muscle mass, prognostic nutritional index (PNI), and biochemical inflammatory markers were assessed. The Kaplan-Meier method and Cox regression analysis were used to analyze overall survival (OS) and progression-free survival (PFS). This study found a disease-specific low muscle mass threshold of LSMI <38.7cm²/m² for women and <45.1cm²/m² for men, with 25.2% of patients having disease-specific low muscle mass. Multivariate cox regression analysis revealed that low PNI was found to be an independent unfavorable prognostic factor for both PFS (HR=0.67; 95% CI: 0.48-0.92, P= 0.015) and OS (HR=0.67; 95% CI: 0.50-0.91, P=0.008). Other factors including ECOG PS 3 (HR=7.76; 95% CI: 1.73-34.76, P=0.007), induction CT (HR=0.66; 95% CI: 0.49-0.88, P= 0.004), and disease-specific low muscle mass (HR=1.40; 95% CI: 1.02-1.92, P= 0.038) also had independent effects on prognosis. The present study provides evidence that the presence of low muscle mass and low PNI significantly impacts the prognosis of patients with stage III NSCLC who undergo definitive CRT. Furthermore, our study is notable for being the first multicenter investigation to identify a disease-specific low muscle mass threshold.

Treatment indicators and prognostic factors in colorectal neuroendocrine neoplasms and adenocarcinoma with neuroendocrine differentiation: a single center retrospective study.

This study compared survival and metastasis occurrence between colorectal neuroendocrine neoplasms (cNEN) and colorectal adenocarcinoma with neuroendocrine differentiation (cNED) and further explored their prognostic factors and treatment indicators. Patients diagnosed as cNEN and cNED in West China Hospital from January 2009 to December 2020 were enrolled. The diagnosis and metastasis rates were calculated. Univariate and multivariate Cox analyses were conducted for progression-free survival (PFS) in cNEN surgical patients, and generalized linear regression was used for metastatic disease. The study enrolled 435 patients, including 257 neuroendocrine tumors (NET), 52 neuroendocrine carcinomas (NEC), 29 mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN), and 97 NED patients, of whom 202 received local resection, and 233 received radical resection. Metastasis rates were higher in MiNEN and NEC groups compared to other groups (NED: 28.9%, MiNEN: 58.6%, NEC: 65.4%, NET: 8.6%, p < 0.001). The liver is the main metastatic site in cNEN, whereas cNED metastasized to various sites. For NEC and MiNEN patients, colon location (p = 0.002) and T stage > 2 (p = 0.040) were associated with disease progression separately. Independent risk factors for metastatic NET included tumor grade G2/G3 (p < 0.001), colon location (p = 0.001), size ≥ 1cm (p = 0.005), and CK20 partial positive (p < 0.001). cNEN show high metastatic capacity and are challenging to diagnose. More aggressive treatment and follow-up strategies are necessary for those patients. NET tumor grade higher than G2, size larger than 1cm, or located in the colon should be managed with radical surgery.

Clinical Outcome Patterns of Use of Radium-223 in Patients with Metastatic Castration-Resistant Prostate Cancer

Introduction: Radium-223 dichloride (radium-223) is a bone-targeting radioisotope therapy that aids in the survival of patients with metastatic castration-resistant prostate cancer (mCRPC) to bones. This study aimed to describe the clinical characteristics and outcomes of patients with mCRPC treated with radium-223 in a real-world setting. Methods: This was a retrospective study of patients with mCRPC treated with radium-223 between 2016 and 2020 at the London Health Sciences Centre in London, Canada. The baseline characteristics between the patients receiving 1–3 and 4–6 treatment cycles were compared using a two-sample t-test and Chi-square test. ANOVA was used to determine if there was a difference in each diagnostic variable per treatment cycle. Kaplan–Meier curves were generated to estimate progression-free survival (PFS) and overall survival in the patients treated with different numbers of cycles. Results: Fifty eligible patients were identified. The median age was 71 years (IQR: 66–76). Most patients (62%) received radium-223 beyond the third-line treatment. The mean number of radium-223 treatments was four. While 60% of the patients received 4–6 injections, 40% received 1–3 injections. Fifty-eight percent (58%) of the patients demonstrated a clinical benefit, with the remainder expressing either disease progression (28%) or stable disease (10%). The patients treated with 4–6 cycles had a delay to disease progression compared to those given 1–3 cycles of radium-223 (F5,35 = 10.52, p &lt; 0.001). A higher alkaline phosphatase level prior to treatment was associated with a longer PFS (z33 = 2.362, p = 0.018). Treatment-related hospitalization for skeletal-related events was noted in 8% of the patients, and 14% required treatment discontinuation due to hematologic toxicity. Conclusions: This study confirms the safety of radium-223 in patients with mCRPC in a real-world setting. The radium-223 treatment was associated with a clinical benefit in the majority of the patients, particularly in those with higher pre-treatment serum alkaline phosphatase levels. Further studies to identify the predictive biomarkers are warranted to better guide the contemporary use of radium-223.

Unmasking Neuroendocrine Prostate Cancer with a Machine Learning-Driven Seven-Gene Stemness Signature That Predicts Progression

Prostate cancer (PCa) poses a significant global health challenge, particularly due to its progression into aggressive forms like neuroendocrine prostate cancer (NEPC). This study developed and validated a stemness-associated gene signature using advanced machine learning techniques, including Random Forest and Lasso regression, applied to large-scale transcriptomic datasets. The resulting seven-gene signature (KMT5C, DPP4, TYMS, CDC25B, IRF5, MEN1, and DNMT3B) was validated across independent cohorts and patient-derived xenograft (PDX) models. This signature demonstrated strong prognostic value for progression-free, disease-free, relapse-free, metastasis-free, and overall survival. Importantly, the signature not only identified specific NEPC subtypes, such as large-cell neuroendocrine carcinoma, which is associated with very poor outcomes, but also predicted a poor prognosis for PCa cases that exhibit this molecular signature, even when they were not histopathologically classified as NEPC. This dual prognostic and classifier capability makes the seven-gene signature a robust tool for personalized medicine, providing a valuable resource for predicting disease progression and guiding treatment strategies in PCa management.

The evolving role of checkpoint inhibitors in the treatment of Hodgkin lymphoma

Since their initial approval as single agent therapy for multiply relapsed/refractory Hodgkin lymphoma (HL), the PD-1 inhibitors nivolumab and pembrolizumab have been incorporated into second-line salvage regimens, and they are being investigated in upfront therapy of newly diagnosed patients. As second-line therapy in combination with brentuximab vedotin or multi-agent chemotherapy, nivolumab and pembrolizumab provide high complete remission rates and durable progression-free survival after consolidative autologous stem cell transplant. Incorporation of these agents into frontline chemotherapy regimens is feasible, and early results from a Phase III trial of nivolumab-AVD compare favorably with the existing standard for advanced stage HL, brentuximab vedotin plus AVD. As nivolumab and pembrolizumab move into earlier lines of HL therapy, open research questions include the efficacy of checkpoint inhibitor regimens in patients who relapse after frontline exposure to nivolumab or pembrolizumab; the selection of patients with relapsed HL who can achieve durable remissions without autologous stem cell transplant; and the efficacy of the PD-1 inhibitors in the frontline therapy of patients with early stage Hodgkin lymphoma.

Body composition derangements in lung cancer patients treated with first-line pembrolizumab: A multicentre observational study.

While immune checkpoint inhibitors (ICIs) are increasingly reshaping the therapeutic landscape of non-small-cell lung cancer (NSCLC), only a limited proportion of patients achieve a relevant and long-lasting benefit with these treatments, calling for the identification of clinical and, ideally modifiable, predictors of efficacy. Body composition phenotypes may reflect aspects of patients' immunology and thereby their ability to respond to ICIs. This study aims to explore the possible association between pre-treatment body composition phenotypes, tumour response, and clinical outcomes in patients receiving first-line pembrolizumab monotherapy for advanced NSCLC. A retrospective review of consecutive patients with treatment-naïve NSCLC and PD-L1 expression ≥50% undergoing pembrolizumab at three academic institutions was performed. Pre-treatment body composition parameters were measured at the third lumbar vertebra level by computed tomography, defined using pre-established cut-offs. Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival and overall survival (PFS and OS), compared through the log-rank test and the Cox proportional hazards model. Data from 134 patients (93 males [69.4%] and 41 females [30.6%]) were collected. Median age was 69years (range 36-85), with a median follow-up of 12months (range 1-131). The median body mass index (BMI) was 24.5 (IQR 21.5; 26.1) kg/m2. Overall, 59.0% and 51.5% of patients met established radiographic criteria for evidence of sarcopenia and myosteatosis, respectively, which occur across the BMI spectrum. Multivariate regression analysis, adjusted for co-morbidities, revealed that sarcopenia (aOR 5.56, 95% CI. 2.46-12.6, P<0.0001) and low intermuscular adipose tissue (IMAT) area (aOR 1.83, 95% CI. 1.22-2.83, P=0.001) were associated with a lower rate of ORR (30.4% vs. 70.5%, P<0.0001 and 30.7% vs. 73.2%, P<0.0001, respectively). Moreover, both in univariate and multivariate analysis, adjusted for co-morbidities, low performance status according to the Eastern Cooperative Oncology Group scale (ECOG PS), sarcopenia and low IMAT were significantly related to short PFS (ECOG PS: aHR 2.73, 95% CI 1.60-4.66, P<0.0001; sarcopenia: aHR 2.24, 95% CI 1.37-3.67, P=0.001; IMAT depot: aHR 2.26, 95% 1.40-3.63, P=0.002) and OS (ECOG PS: aHR 3.44, 95% CI 1.96-6.01, P<0.0001; sarcopenia: aHR 4.68, 95% CI 2.44-8.99, P<0.0001; IMAT depot: aHR 3.18, 95% 1.72-5.88, P<0.0001). Skeletal muscle abnormalities, apparently frequent in NSCLC, potentially represent intriguing predictive markers of response to ICIs and survival outcomes. Large prospective trials are needed to validate ICIs responders' clinical biomarkers.

Efficacy and Safety of Anti-EGFR Therapy Rechallenge in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

Colorectal cancer (CRC) represents the second leading cause of cancer-related mortality worldwide, with a significant portion of patients presenting with metastatic disease at diagnosis. Resistance to initial anti-EGFR therapy, a key treatment for RAS wild-type metastatic CRC, remains a major challenge. This study aimed to assess the efficacy and safety of rechallenge with anti-EGFR therapy in patients with metastatic CRC who have progressed after prior treatments. A systematic search was conducted across PubMed, Web of Science, Cochrane, and Scopus. Studies were included if they were randomized controlled trials (RCTs) or observational studies involving patients with EGFR-mutated metastatic CRC who received anti-EGFR therapy as a rechallenge. Endpoints included objective response rate (ORR), disease control rate (DCR), and the incidence of adverse events. Statistical analyses were performed using the DerSimonian/Laird random effect model, with heterogeneity assessed via I2 statistics. R, version 4.2.3, was used for statistical analyses. Fourteen studies were included with 520 patients; 50.3% were male, and the median age was 63years old. The median progression-free survival (mPFS) ranged between 2.4 and 4.9months, while the median overall survival (mOS) ranged from 5 to 17.8months. Our pooled analysis demonstrated an objective response rate (ORR) of 17.70% (95% CI, 8.58-26.82%) and a disease control rate (DCR) of 61.72% (95% CI, 53.32-70.11%), both with significant heterogeneity (I2, 84% and 80%, respectively; p < 0.01). In the subgroup analysis, cetuximab showed an ORR of 18.31% (95% CI, 4.67-31.94%), and panitumumab an ORR of 10.9% (95% CI, 0.00-26.82%), while the combination of both resulted in an ORR of 29.24% (95% CI, 0.00-65.84%). For DCR, cetuximab resulted in 62.1% (95% CI, 49.32-74.87%), panitumumab in 63.05% (95% CI, 52.13-73.97%), and the combination in 60.34% (95% CI, 31.92-88.77%), all with significant heterogeneity. Adverse events included anemia (15.39%), diarrhea (4.20%), hypomagnesemia (6.40%), neutropenia (22.57%), and skin rash (13.22%). Rechallenge with anti-EGFR therapy in metastatic CRC patients shows moderate efficacy with manageable safety profiles. These findings highlight the need for careful patient selection and monitoring to optimize outcomes. Further studies are warranted to refine strategies for maximizing the therapeutic benefits of anti-EGFR rechallenge.

Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation

BackgroundTP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab. Obinutuzumab 1000mg was given on cycle 1 day 1, 8, 15 and day 1 of cycles 2-8. After 2 cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease using an immunosequencing assay, treatment was discontinued. The primary endpoint was met if ≥11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD5 and uMRD6 at cycle 13 was 95% (18/19) and 84% (16/19). With median follow up of 28.2 months, the primary endpoint was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant mantle cell lymphoma. These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483

The Effect of Androgen Deprivation Therapy on the Cardiovascular System in Advanced Prostate Cancer

Androgen deprivation therapy (ADT) is a mainstay treatment for metastatic prostate cancer, improving progression-free survival. ADT suppresses the production of testosterone and reduces circulating levels of the hormone. Luteinizing hormone-releasing hormone (LH-RH) agonists are the most commonly used ADT modality. They can be given alone or in combination with androgen synthesis inhibitors or androgen receptor antagonists. An estimated 40% of prostate cancer patients will receive ADT as part of their therapy during their lifetime. However, ADT has numerous adverse effects, including an increased cardiovascular risk that impacts quality of life. Relugolix is an alternative form of ADT. It is the only oral gonadotropin-releasing hormone antagonist, circumventing injection site reactions, making it easier for patients to take, and thus increasing compliance. Testosterone suppression with relugolix is excellent and testosterone recovery after discontinuation is rapid. This paper reviews the ADT and anti-androgen treatment options for men with prostate cancer and the cardiovascular effects of these therapies. There is accumulating evidence that cardiovascular risk with relugolix is lower than with other ADT medications and also lower than with androgen synthesis inhibitors and androgen receptor antagonists. This paper provides insight into the use of different ADT regimens based on the cardiovascular status and circumstances. It explores strategies to mitigate negative cardiovascular consequences and highlights the need for further study.

Phase 2 Study of Palbociclib in Patients with Tumors with CDK4 or CDK6 Amplification: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol Z1C.

Amplification of CDK4 and CDK6 is a feature of a variety of malignancies, and preclinical evidence suggests inhibition of CDK4/6 is a plausible treatment strategy in these tumors. Subprotocol Z1C of the NCI-MATCH trial was designed to evaluate the CDK4/6 inhibitor palbociclib in CDK4- or CDK6-amplified tumors. Patients had a solid malignancy with progression on at least one systemic therapy for advanced disease. Tumors with ≥ 7 copies of CDK4 or CDK6 were considered amplified and molecularly eligible. Enrolled patients were treated with palbociclib 125 mg daily on days 1-21 of a 28-day cycle. The primary endpoint was ORR. Forty-three patients were enrolled on subprotocol Z1C, and 38 patients were deemed eligible, treated, and included in analyses; 25 patients were eligible, treated, and centrally confirmed to have CDK4 or CDK6 amplification and comprised the primary analysis cohort for ORR endpoint. Among the 25 patients in the primary cohort, one patient had a PR, 4 patients had SD, and 16 patients had PD as best response. Four patients were not evaluable due to lack of follow-up scans. Among the 38 evaluable patients, one patient had a PR, 10 patients had SD, and 21 patients had PD as best response. Partial response and stable disease were only seen in patients with CDK4 amplification. Median progression-free survival was 2.0 months, and median overall survival was 8.8 months. Palbociclib showed limited activity in histology-agnostic CDK4- or CDK6-amplified tumors, though CNS tumors may be worthy of future investigation.

Reappraisal of prognostic factors in CNS WHO grade 3 oligodendrogliomas IDH-mutant and 1p/19q co-deleted: lessons from the French POLA cohort.

In POLA cohort, three pathological groups of CNS WHO grade 3 oligodendroglioma IDH-mutant and 1p/19q co-deleted have been described: group 1 (high mitotic count only), group 2 (microvascular proliferation MVP and no necrosis), and group 3 (MVP and necrosis). 494 patients from the POLA cohort, with a median follow up of 96 months were included. To identify the impact of the pathological groups and contrast enhancement in group 1 on overall survival (OS) or progression free survival (PFS), survival curves were obtained (Kaplan-Meier method) and compared (log-rank test). Prognostic value of clinical factors and CDKN2A homozygous deletion HD were also tested. Multivariate analysis was performed. Survival analysis demonstrated that the pathological groups were associated with both progression-free survival (PFS P=0.01) and overall survival (OS P=0.001). In group 1, patients with contrast enhancement (1CE+) had a poorer prognosis compared to those without (OS P=0.028, PFS P=0.006). Further stratification into group 1CE-, group 1CE+, group 2, and group 3 provided clearer prognostic distinctions (OS P=0.002, PFS P<0.0001). Other prognostic factors included age (OS P<0.0001, PFS P=0.002), extent of surgical resection (OS P=0.001, PFS P=0.003), KPS (OS P<0.0001, PFS P=0.002), postoperative treatment (OS P=0.007, PFS P<0.0001), and CDKN2A HD (OS and PFS P<0.0001). The pathological groups remained of prognostic significance for PFS in multivariate analysis. Necrosis and CDKN2A HD are adverse prognostic factors of WHO grade 3 oligodendrogliomas, IDH mutant and 1p/19q co-deleted. Besides, in group 1 patients, lack of contrast enhancement is a factor of better prognosis.